Process for preparing 4,6-diaminopyrimido[5,4-d]pyrimidines

ABSTRACT

A process for preparing 4,6-diaminopyrimido[5,4-d]pyrimidines of formula I,  
                 
 
     wherein  
     R 1  denotes a hydrogen atom or a C 1 -C 6  alkyl group,  
     R 2  denotes an optionally substituted C 6 -C 10  aryl group,  
     R 3  denotes a hydrogen atom or a C 1 -C 6  alkyl group, and  
     R 4  denotes a hydrogen atom or an optionally substituted C 1 -C 6  alkyl, C 3 -C 6  alkenyl, C 3 -C 8 cycloalkyl or a 4- to 7-membered, nitrogen-containing heterocyclyl group, or R 3  and R 4  together with the nitrogen atom linked to them denote an optionally substituted heterocyclyl group.

RELATED APPLICATIONS

[0001] Benefit of U.S. Provisional Application Serial No. 60/289,879,filed on May 9, 2001, is hereby claimed.

FIELD OF THE INVENTION

[0002] The invention relates to a process for preparing4,6-diaminopyrimido[5,4-d]pyrimidines of formula I,

[0003] wherein R¹, R², R³, and R⁴ are defined as specified, from acompound of formula II,

[0004] wherein R¹, R², R³, and R⁴ are defined as specified and PG¹denotes a suitable protecting group.

BACKGROUND TO THE INVENTION

[0005] 4,6-diaminopyrimido[5,4-d]pyrimidines are known for example fromWO 97/32880 and are valuable pharmaceutical compositions which have, inparticular, an inhibitory effect on signal transduction mediated bytyrosine kinases.

[0006] However, the method of preparation described therein isunsuitable for production on an industrial scale as the desired productsare described as being obtained from starting materials which are noteasily accessible, such as4-anilino-6-methylsulphinyl-pyrimido[5,4-d]pyrimidines or4-anilino-6-methylsulphonylpyrimido[5,4-d]pyrimidines which, whenreacted, give off foul-smelling and toxic thiols which lead tocontamination of the products.

[0007] The aim of the present invention is therefore to provide aprocess which makes it possible to synthesise, work up, purify andisolate 4,6-diaminopyrimido[5,4-d]pyrimidines of formula I on anindustrial scale while overcoming the disadvantages mentioned above.

DETAILED DESCRIPTION OF THE INVENTION

[0008] Surprisingly, it has been found that4,6-diaminopyrimido[5,4-d]pyrimidines of formula I

[0009] wherein

[0010] R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group,

[0011] R² denotes an optionally substituted C₆-C₁₀ aryl group,

[0012] R³ denotes a hydrogen atom or a C₁-C₆ alkyl group, and

[0013] R⁴ denotes a hydrogen atom or an optionally substituted C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₈ cycloalkyl or a 4- to 7-membered,nitrogen-containing heterocyclyl group, or

[0014] R³ and R⁴ together with the nitrogen atom linked to them denotean optionally substituted heterocyclyl group,

[0015] can be prepared in high yields and in a comparatively smallnumber of steps, if the compound of formula II wherein R¹, R², R³, andR⁴ are as herein defined and

[0016] PG¹ denotes a suitable protecting group,

[0017] (a) after the protecting group has been cleaved,

[0018] (b) is treated with a reducing agent, and

[0019] (c) is treated with an oxidising agent.

[0020] The invention thus relates to a process for preparing thecompounds of formula I.

[0021] The invention further relates to a process for preparing acompound of formula II, by reacting a compound of formula III,

[0022] wherein R¹, R² and PG¹ are as herein defined,

[0023] with an amine of formula IV,

R³R⁴NH  (IV)

[0024] wherein R³ and R⁴ are as herein defined,

[0025] optionally in the presence of a base.

[0026] The invention further relates to a process for preparing acompound of formula III, wherein a compound of formula V,

[0027] wherein R¹ and R² are as herein defined, is provided with asuitable protecting group (PG¹).

[0028] The invention also relates to a process for preparing thecompounds of formula V by reducing a compound of formula VI,

[0029] wherein R¹ and R² are as herein defined; and a process forpreparing a compound of formula VI by reacting2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine with an amine of formulaVIII,

R¹R²NH  (VIII)

[0030] wherein R¹ and R² are as herein defined.

[0031] The invention further relates to the new intermediate products offormulae II, III, V and VI.

[0032] The term “alkyl” as used hereinbefore and hereinafter withrespect to the groups R¹, R³ and/or R⁴ denotes a straight-chain orbranched alkyl group having up to 6 C-atoms, preferably 1 to 4 C-atoms.Methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl areparticularly preferred.

[0033] The term “alkenyl” as used hereinbefore and hereinafter withrespect to the group R⁴ denotes a straight-chain or branched alkenylgroup having up to 6 C-atoms, preferably 3 to 5 C-atoms. Allyl,but-2-enyl, but-3-enyl, pent-2-enyl, pent-3-enyl and pent-4-enyl areparticularly preferred.

[0034] The term “aryl” as used hereinbefore and hereinafter with respectto the group R² denotes an aromatic hydrocarbon group with 6 to 10C-atoms, and aryl preferably denotes phenyl or naphthyl.

[0035] The term “suitable protecting group” as used hereinbefore andhereinafter with respect to the group PG¹ denotes a group familiar tothose skilled in the art, e.g. a protecting group for amino groups asdescribed in “Protective Groups in Organic Chemistry”, edited by J. F.W. McOmie (Plenum Press), which is easily introduced, is inert to thesubsequent reactions and can easily be cleaved again. Preferredprotecting groups are the acetyl, trifluoroacetyl, benzoyl,ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,methoxybenzyl, mesyl, tosyl or 2,4-dimethoxybenzyl group.

[0036] A protecting group used is cleaved hydrolytically, for example inan aqueous solvent, e.g. in water, isopropanol/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide or by ether splitting, e.g. in thepresence of iodotrimethylsilane, at temperatures between 0 and 100° C.,preferably at temperatures between 10 and 50° C.

[0037] A benzyl, methoxybenzyl or benzyloxycarbonyl is preferablycleaved by hydrogenolysis, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid optionally with the addition of an acid such ashydrochloric acid at temperatures between 0 and 50° C., but preferablyat ambient temperature, and at a hydrogen pressure of 1 to 7 bar,preferably from 3 to 5 bar.

[0038] A methoxybenzyl group can also be cleaved in the presence of anoxidising agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesbetween 0 and 50° C., but preferably at ambient temperature. However, a2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acidin the presence of anisol. A tert-butyloxycarbonyl group is preferablycleaved by treating with an acid such as trifluoroacetic acid orhydrochloric acid, optionally using a solvent such as methylenechloride, dioxane or ether.

[0039] The term “heterocyclyl group” as used hereinbefore andhereinafter with respect to the group R³ or the group formed by R³ andR⁴ with the enclosed nitrogen atom denotes a saturated or unsaturated 4-to 7-membered, nitrogen-containing heterocyclyl group which mayoptionally contain, in addition to carbon atoms and at least onenitrogen atom, other heteroatoms selected from among oxygen and sulphur.The following heterocyclyl groups are preferred:

[0040] saturated 5- or 6-membered heterocyclyl groups which

[0041] contain one or two nitrogen atoms, particularly pyrrolidine,piperidyl and piperazyl, or

[0042] contain one nitrogen atom and an oxygen or sulphur atom,particularly morpholino and thiomorpholino.

[0043] If one of the groups R¹ to R⁴ is referred to as an “optionallysubstituted” group, this group may have one or more substituents,preferably 1, 2 or 3, particularly 1 or 2 substituents. Thesesubstituents are groups which are inert under the reaction conditions ofthe process according to the invention and do not provoke any noticeableside reactions. Preferred substituents are selected from among fluorine,chlorine, bromine, carboxy, carboxy-C₁₋₃-alkyl, carboxy-C₁₋₃-alkoxy,alkoxycarbonyl-C₁₋₃-alkoxy, cyano, trifluoromethoxy, trifluoromethyl,C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy, thiol, C₁₋₃-alkylthio,phenyl-C₁₋₃-alkoxy, amino, amino-C₁₋₃-alkyl, C₁₋₃-alkylaminoC₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino anddi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl.

[0044] In a preferred embodiment the groups R¹ to R⁴ have the followingmeanings:

[0045] R¹ denotes hydrogen or methyl, particularly hydrogen,

[0046] R² denotes phenyl which may be substituted by one or two halogenatoms, particularly fluorine and/or chlorine, particularly3-chloro-4-fluorophenyl,

[0047] R³ denotes hydrogen or methyl, particularly hydrogen, and

[0048] R⁴ denotes a 5- or 6-membered, nitrogen-containing heterocyclewhich may be substituted by one or two C₁₋₃-alkyl groups, particularly1-methylpiperid-4-yl, or

[0049] R³ and R⁴ together with the enclosed nitrogen atom form a 5- or6-membered, nitrogen-containing heterocycle which may be substituted byone or two groups selected from among amino, C₁₋₃-alkyl anddi-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, particularly amino, methyl anddiethylaminomethyl, most preferably 4-amino-4-methylpiperid-1-yl.

[0050] In a preferred embodiment of the process according to theinvention for preparing the compound of formula I:

[0051] in step (b) the compound obtained after the protecting group hasbeen cleaved is hydrogenated in the presence of a transition metalcatalyst or with hydrogen iodide optionally in the presence ofphosphorus;

[0052] in step (c) the compound obtained in step (b) is treated with aperoxodisulphate or hydrogen peroxide.

[0053] Stage II→I

[0054] Step (a)

[0055] The reaction of the compound of formula II, wherein PG¹ is a C₁₋₆alkylcarbonyl group, with an aqueous base, preferably an alkali metalbase such as lithium hydroxide, sodium hydroxide or potassium hydroxide,is generally carried out at a temperature of 0° C. to 150° C.,preferably 10° C. to 100° C., particularly at about 40 to 80° C.,optionally in the presence of an inert solvent, such as for exampletoluene or tetrahydrofuran and a protic solvent such as for example analcohol or water or mixtures thereof. Preferably, 0.8 to 2, particularly0.9 to 1.2 equivalents of the base are used to 1 equivalent of thecompound of formula II.

[0056] In a particularly preferred embodiment about 0.9 to 1.1equivalents of the sodium hydroxide in the form of an approximately 2 Naqueous solution are added at ambient temperature to a mixture of oneequivalent of the compound of formula II and 5 to 20 parts methanol and0.5 to 2 parts tetrahydrofuran (THF) based on 1 part compound of formulaII and the mixture is heated to boiling for about 30 minutes to 2 hours.The mixture obtained is cooled and then further processed in the nextstep (b) without any other purification.

[0057] Step (b)

[0058] Dechlorination, Variant A:

[0059] The compound obtained after the protecting group has been cleavedis generally hydrogenated in the presence of a transition metalcatalyst. The hydrogenation is generally carried out at a temperature of20° C. to 150° C., preferably 40° C. to 120° C., particularly at theboiling temperature of the diluent, at a hydrogen pressure of about1-120 bar, in the presence of an ether, such as for examplediethylether, tert-butyl-methylether, dioxane or tetrahydrofuran, analcohol, such as for example methanol, ethanol or isopropanol, ahydrocarbon, such as for example cyclohexane or n-hexane or mixturesthereof, particularly in the presence of the diluent obtained from step(a). Instead of the hydrogen formic acid may also be used as thehydrogen donor. In this case the reaction is generally carried out atnormal pressure and 5 to 20 parts formic acid are used to 1 part of thecatalyst. Preferably, 0.01 to 0.90, particularly 0.01 to 0.10 parts of acatalyst consisting of palladium and activated charcoal is used,containing 1 to 25%, preferably 5 to 15% palladium, to 1 part of thecompound obtained after the protecting group has been cleaved. Thehydrogenation is generally complete under the conditions described after1 to 100 hours, preferably 10 to 80 hours. The crude product obtained isfurther processed in the next step after distillation of the solvent butno other purification.

[0060] In a particularly preferred embodiment the mixture obtained instep (a) is evaporated to dryness and the residue is taken up in THF andmethanol. Pd/C (5-15%) is added and the mixture is refluxed. After theaddition of 2 to 20 ml of formic acid, the mixture is stirred for 20 to75 hours. It is left to cool to ambient temperature, filtered andevaporated to dryness. The residue is suspended in water and ethylacetate, made weakly basic with a concentrated ammonia solution andstirred. The crystalline product is isolated, optionally recrystallisedand dried.

[0061] Dechlorination, Variant B:

[0062] Alternatively, the compound obtained after the protecting grouphas been cleaved may be treated with hydrogen iodide, optionally in thepresence of phosphorus. The reaction is generally carried out at atemperature of 20° C. to 150° C., preferably 40° C. to 120° C.,particularly at the boiling temperature of the diluent, in the presenceof a polar solvent, particularly a carboxylic acid, such as for exampleacetic acid or propionic acid, or an aqueous inorganic acid such as forexample hydrochloric acid, hydrobromic acid, hydriodic acid or mixturesthereof or water. The reaction is generally carried out at normalpressure, preferably using 6 to 6.5 equivalents of hydrogen iodide inthe form of a 30- to 60% aqueous solution based on 1 equivalent of thecompound obtained after the protecting group has been cleaved.Preferably, the reaction is carried out in the presence of redphosphorus, using 1.0 to 3.0, preferably 1.8 to 2.5 equivalentsphosphorus based on 1 equivalent of the compound obtained after theprotecting group has been cleaved. The reaction is generally completeunder the conditions specified after 0.5 to 10 hours, preferably 1 to 8hours. The crude product obtained is further processed in the next stepafter distillation of the solvent but no other purification.

[0063] In a particularly preferred embodiment the mixture obtained instep (a) is evaporated down, taken up in glacial acetic acid and addeddropwise to a suspension of red phosphorus in hydriodic acid (57%). Themixture is refluxed for 3 to 5 hours, decolorised and neutralised. Theproduct is isolated and dried.

[0064] Step (c)

[0065] The compound obtained in step (b) is preferably oxidised in thepresence of an aqueous acid with a peroxodisulphate or hydrogenperoxide. The oxidation is generally carried out at a temperature of 0°C. to 150° C., preferably 40° C. to 120° C., particularly at the boilingtemperature of the diluent, in the presence of an acid, such as forexample acetic acid, trifluoroacetic acid, hydrochloric acid, nitricacid, phosphoric acid or sulphuric acid or mixtures thereof,particularly in the presence of water. Preferably, 0.8 to 2,0.particularly 0.9 to 1.5 equivalents of the oxidising agent are used,particularly in the form of a 20 to 40% aqueous solution of hydrogenperoxide or a 20- to 50% aqueous solution of sodium peroxodisulphatebased on one equivalent of the compound obtained in step (b). Theoxidation is generally complete under the conditions specified after 10minutes to 30 hours, preferably 15 minutes to 24 hours. The crudeproduct obtained is further processed in the next step afterdistillation of the solvent but no other purification.

[0066] In a particularly preferred embodiment 1 equivalent of thecompound obtained in step (b) is taken up in 5 to 15% sulphuric acid andat boiling temperature combined with 0.01 to 0.10 equivalents ofpotassium iodide and 1.0 to 2.0, preferably 1.2 to 1.5 equivalents ofhydrogen peroxide in the form of a 35% solution. The mixture is stirredfor 10 to 30 minutes and an aqueous solution of sodium bisulphite andethanol is added. Then the mixture is allowed to cool slowly to ambienttemperature and stirred. The product that crystallises out is filteredand dried.

[0067] In another particularly preferred embodiment 1 equivalent of thecompound obtained in step (b) is taken up in a mixture of glacial aceticacid and water (20- to 40%) and combined with 1.0 to 2.0, preferably 1.1to 1.6 equivalents of sodium peroxodisulphate in the form of anapproximately 30 to 35% aqueous solution. The mixture is stirred for 30to 300 minutes at a temperature of 20 to 75° C. The solid formed isfiltered off, suspended in water, neutralised with concentrated ammoniasolution and extracted with ethyl acetate. The organic phase isseparated off, dried and evaporated down. The residue is taken up inethanol and converted into the hydrochloride of the compound of formulaI by the addition of ethanolic HCl. The crystallised product is filteredoff and dried.

[0068] Stage III→II

[0069] In a preferred embodiment of the process according to theinvention for preparing the compound of formula II:

[0070] the reaction is carried out in the presence of a tertiary amine;

[0071] the reaction is carried out in a temperature range of 0° C. to150° C.

[0072] The reaction with the amine of formula IV is expediently carriedout in a diluent such as methanol, ethanol, isopropanol, butanol,tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide,dimethylsulphoxide, ethyleneglycolmonomethylether,ethylenglycoldiethylether or sulpholane or mixtures of these diluents,optionally in the presence of an inorganic base, e.g. sodium carbonateor potassium hydroxide, or a tertiary organic base, e.g. triethylamine,N-ethyl-diisopropylamine or pyridine, while the latter maysimultaneously serve as solvent, and optionally in the presence of areaction accelerator such as a copper salt, a correspondingamino-hydrohalide or alkali metal halide at temperatures between 0 and150° C., but preferably at temperatures between 20 and 120° C. Thereaction may however also be carried out without a solvent or in anexcess of the compound of general formula IV used. The reaction isgenerally carried out at normal pressure, using 0.8 to 2.0, preferably0.9 to 1.5, particularly 1.0 to 1.5 equivalents of a compound of formulaIV based on 1 equivalent of the compound of formula III. The reaction isgenerally complete under the conditions specified after 15 to 600minutes, preferably 30 to 180 minutes. The crude product obtained isgenerally purified by recrystallisation or may be further processed inthe next step without any other purification.

[0073] In a particularly preferred embodiment 0.8 to 1.8, preferably 1.0to 1.6 equivalents of the amine of formula IV, particularly1-methyl-4-aminopiperidine or 4-methylpiperidin-4-ylamine, is addeddropwise to a mixture of 1 equivalent of the compound of formula III,THF and/or methanol and optionally 1 to 2 equivalents of triethylamineat ambient temperature. The mixture is stirred for 10 to 90 minutes at20 to 80° C. After cooling, water is added and the mixture is stirred.The product that crystallises out is filtered off, washed with water anddried. After recrystallisation from ethyl acetate it is filtered anddried.

[0074] Stage V→III

[0075] In a preferred embodiment of the process according to theinvention for preparing the compound of formula III:

[0076] the compound of formula V is reacted with a C₁₋₆ carboxylic acidor a reactive derivative thereof in the presence of a base, preferably aC₁₋₆ carboxylic acid chloride in the presence of a tertiary amine,particularly acetyl chloride, in the presence ofN-ethyldiisopropylamine.

[0077] The acylation is expediently carried out with a correspondinghalide or anhydride in a solvent such as methylene chloride, chloroform,carbon tetrachloride, ether, tetrahydrofuran, ethyl acetate, dioxane,benzene, toluene, acetonitrile or sulpholane optionally in the presenceof an inorganic or organic base, preferably a tertiary amine attemperatures of −20 to 150° C., preferably at temperatures from −10 to120° C., particularly at ambient temperature. However, it may also becarried out with the free acid, optionally in the presence of anacid-activating agent or a dehydrating agent, e.g. in the presence ofisobutyl chloroformate, thionylchloride, trimethylchlorosilane, hydrogenchloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonicacid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxybenzotriazole, N,N′-carbonyldiimidazole orN,N′-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, attemperatures between −20 and 200° C., but preferably at temperaturesbetween −10 and 160° C. The reaction is generally carried out at normalpressure, using 0.8 to 2.0, preferably 0.9 to 1.5, particularly 1.0 to1.5 equivalents of a carboxylic acid derivative, based on 1 equivalentof the compound of formula V. The reaction is generally complete underthe conditions specified after 15 to 300 minutes, preferably 30 to 120minutes. The crude product obtained is generally purified byrecrystallisation or may be further processed in the next step withoutany other purification.

[0078] In a particularly preferred embodiment 1.1 to 1.5, particularlyabout 1.3 equivalents of acetylchloride are added dropwise to a mixtureof 1 equivalent of formula V, N-ethyldiisopropylamine and ethyl acetateat 0 to 20° C. The mixture is stirred for 60 to 120 minutes at ambienttemperature and washed with water at 40 to 90° C. The product isrecrystallised from ethanol, filtered off and dried.

[0079] Stage VI→V

[0080] In a preferred embodiment of the process according to theinvention for preparing the compound of formula V:

[0081] the compound of formula VI is reduced with a boranate,particularly with sodium boranate in the presence of a base and a polarsolvent.

[0082] The reduction may be carried out by catalytic hydrogenation withhydrogen in the presence of a catalyst such as palladium/charcoal orplatinum in a solvent such as methanol, ethanol, ethyl acetate,dimethylformamide, dimethylformamide/acetone or glacial acetic acid,optionally with the addition of an acid such as hydrochloric acid attemperatures between 0 and 50° C., but preferably at ambienttemperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar.

[0083] Preferably, the reduction is carried out with a boranate selectedfrom among lithium boranate, sodium boranate and potassium boranate,expediently in a diluent such as water, methanol, ethanol, isopropanol,butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene,dimethylformamide, dimethylsulphoxide, ethyleneglycolmonomethylether,ethyleneglycoldiethylether or sulpholane or mixtures of these diluents,optionally in the presence of an inorganic base, e.g. sodium carbonate,sodium hydroxide or potassium hydroxide, or a tertiary organic base,e.g. triethylamine, N-ethyldiisopropylamine or pyridine, at temperaturesof −20 to +60° C., preferably −10 to +20° C. The reaction is generallycarried out at normal pressure using 0.9 to 4.0, preferably 1.1 to 1.9,more particularly 1.6 to 1.8 mol of a boranate, based on 1 mol of thecompound of formula VI. The reaction is generally complete under theconditions specified after 15 to 600 minutes, preferably 60 to 240minutes. The crude product obtained is generally purified byrecrystallisation or may be further processed in the next step withoutany other purification.

[0084] In a particularly preferred embodiment a mixture of about 1.75mol sodium borohydride, water and sodium hydroxide in the form of anapproximately 2N sodium hydroxide solution is added dropwise to amixture of 1 mol of a compound of formula VI and ethyl acetate at 0 to5° C. The mixture is stirred for another 1 to 3 hours at 0 to 20° C. andthen heated to 60 to 80° C. The suspension is filtered and cooled toabout 0° C. The product that crystallises out is isolated and dried.

[0085] Tetrachlorohomopurine Stage→VI

[0086] The reaction with the amine of formula VII is expediently carriedout in a diluent such as methanol, ethanol, isopropanol, butanol,tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide,dimethylsulphoxide, ethyleneglycolmonomethylether,ethyleneglycoldiethylether, sulpholane or water or mixtures of thesediluents, particularly THF, optionally in the presence of an inorganicbase, e.g. sodium carbonate or potassium hydroxide, or a tertiaryorganic base, e.g. triethylamine, N-ethyldiisopropylamine or pyridine,at temperatures of 0 to 80° C., preferably 5 to 50° C., particularly 10to 30° C. The reaction is generally carried out at normal pressure,using 0.7 to 1.2, preferably 0.8 to 1.0, particularly about 0.95equivalents of a compound of formula VII based on 1 equivalent ofwater-dampened tetrachlorohomopurine. The reaction is generally completeunder the conditions specified after 15 to 600 minutes, preferably 30 to180 minutes. The crude product obtained is generally purified byrecrystallisation or may be further processed in the next step withoutany other purification.

[0087] In a particularly preferred embodiment, a solution of 0.8 to 0.95equivalents of the amine of formula VII, particularly3-chloro-4-fluoraniline in THF, is added dropwise to a mixture of 1equivalent of tetrachlorohomopurine and tetrahydrofuran at 10 to 20° C.The mixture is stirred for 10 to 50 minutes at ambient temperature,activated charcoal is added and stirring is continued for another 10 to20 minutes at ambient temperature. Then the reaction mixture is filteredin water and the filter residue is washed with THF. The aqueoussuspension is stirred at ambient temperature and the product is thenisolated and dried.

[0088] A major advantage of the process according to the invention isthat it enables the compounds of formula I to be produced on anindustrial scale starting from an easily obtainable starting material,namely 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine(tetrachlorohomopurine).

[0089] Other advantageous aspects of the method according to theinvention are the high space/time yields of the present process and thehigh yield and purity of the associated intermediate products, which canbe further processed without being purified by chromatography.

[0090] The Examples that follow serve to illustrate the processescarried out by way of example for preparing the compound of formula I.They are to be understood as being possible methods given solely asexamples without restricting the invention to their content.

EXAMPLE 1 (3-chloro-4-fluorophenyl)-(2,6,8-trichloropyrimido[5,4-d]pyrimidin-4-yl)amine (1)

[0091] At 15° C. a solution of 72.78 g (0.5 mol) of3-chloro-4-fluoroaniline in 200 ml of THF is added dropwise to asuspension of 269.3 g of water-dampened tetrachlorohomopurine (about50%, corresponding to about 0.5 mol) in 1820 ml of tetrahydrofuran(THF). The mixture is stirred for 30 minutes at ambient temperature,13.5 g of activated charcoal are added and stirring is continued foranother 15 minutes at ambient temperature. Then the reaction mixture isfiltered in 4.1 l of water and the filter residue is washed with 200 mlof THF. The aqueous suspension is stirred for 30 minutes at ambienttemperature and the product is then filtered off and dried in vacuo.Yield: 189 g (99.7%, based on the aniline), melting point 229.6° C.

[0092] 250 MHz-¹H-NMR (CDCl₃) (ppm)=8,83 br s, 1H, NH; 7.95 dd, 1H,aniline-H; 7,69 ddd, 1H, aniline-H; 7,19 dd, 1H, aniline-H.

EXAMPLE 2(3-chloro-4-fluorophenyl)-(2,6-dichloro-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl)amine(2)

[0093] At 2° C. a solution of 191.99 g (5.079 mol) of sodium borohydridein 520 ml of water and 22 ml of 2N sodium hydroxide solution is addeddropwise to a suspension of 1100 g (2.902 mol) of (1) in 22 l of ethylacetate. The mixture is stirred for 2 hours at 10° C. and then heated to71° C. The suspension is filtered through Celite and cooled to 0° C. Theproduct that crystallises out is filtered off and dried at 40° C. untila constant weight is attained.

[0094] Yield: 957.1 g (95,2%). melting point: 227.4° C.

[0095] 250-MHz-¹H-NMR (DMSO) (ppm)=9.15 br s, 1H, NH; 8,79 br s, 1H, NH;8.,00, dd, 1H, aniline-H; 7.73 ddd, 1H, aniline-H; 7.39 t, 1H,aniline-H; 4.55 s, 2H, CH₂.

EXAMPLE 31-[2,6-Dichloro-8-(3-chloro-4-fluorophenylamino)-4H-pyrimido[5,4-d]pyrimidin-3-yl]ethanone(3)

[0096] At 10° C., 56.4 ml (0.789 mol) of acetylchloride are addeddropwise to a suspension of 210.6 g (0.608 mol) of (2) and 176 ml ofN-ethyldiisopropylamine (0.95 mol) in 2.1 l of ethyl acetate. Themixture is stirred for 90 minutes at ambient temperature and then washed3 times with 700 ml of water at 60° C. The organic phase is evaporateddown and combined with 590 ml of ethanol. The mixture is briefly broughtto boiling point, cooled to 0-5° C. and stirred at this temperature for30 minutes. The product that crystallises out is filtered off and driedat 60° C. in vacuo. Yield: 180.3 g (76.3%), melting point: 177.6° C.

[0097] 250 MHz-¹H-NMR (CDCl₃) (ppm)=7,80 dd, 1H, aniline-H; 7,70 s, 1H,NH; 7,55 ddd, 1H, aniline-H; 7,15 t, 1H, aniline-H; 4,89 s, 2H, CH₂;2,51 s, 3H, CH₃.

EXAMPLE 41-[6-chloro-8-(3-chloro-4-fluorophenylamino)-2-(1-methylpiperidin-4-ylamino)-4H-pyrimido[5,4-d]pyrimidin-3-yl]ethanone(4)

[0098] 47.2 g (0.413 mol) of 1-methyl-4-aminopiperidine is addeddropwise at ambient temperature to a mixture of 123.3 g (0.317 mol) of(3), 740 ml of THF and 61.7 ml (0.445 mol) of triethylamine. The mixtureis stirred for 30 min at 50° C. It is left to cool to 40° C., 1480 ml ofwater are added and the mixture is then stirred for 90 minutes at 10° C.The product that crystallises out is filtered off, washed with 150 ml ofwater and dried in vacuo at 60° C. The product is dissolved in 1150 mlof ethyl acetate at boiling temperature. It is cooled to 10° C.,filtered and the product that crystallises out is dried at 60° C. invacuo.

[0099] Yield: 128.9 g (87.2%).

[0100] 250-MHz-¹H-NMR (CDCl₃) (ppm)=8,70 br s, 1H, NH; 7.80 dd, 1H,aniline-H; 7,72 s, 1H, NH; 7,50 ddd, 1H, aniline-H; 7.13 t, 1H,aniline-H; 4,75 s, 2H, CH₂; 4,03-3,87 CH₂CHNCH₂; 2,82-2,65 m, 2H,CH₂CH₂N; 2,38 s, 3H, CH₃; 2,33 s, 3H, CH₃; 2,33-2,19 m, 2H, CH₂CH₂N;2,18-2,02 m, 2H, CHCH₂CH₂; 1,75-1,60 m, 2H, CHCH₂CH₂.

EXAMPLE 58-(3-chloro-4-fluorophenylamino)-2-(1-methylpiperidin-4-ylamino)pyrimido[5,4-d]pyrimidine(5)

[0101] 9 ml of 2N sodium hydroxide solution are added to a mixture of 9g (0.019 mol) of (4), 81 ml of methanol and 9 ml of THF and the mixtureis refluxed for 1 hour. Then 0.45 g of Pd/C (10%) are added and 4.5 mlof formic acid are added dropwise at boiling temperature. The mixture isrefluxed for 24 hours, filtered off and evaporated down in vacuo toleave a residue. This is taken up in 90 ml of water and 7.2 ml of conc.hydrobromic acid and combined at ambient temperature with 3.9 ml ofhydrogen peroxide (30%). The mixture is stirred for 5 hours at ambienttemperature, then the product that crystallises out is filtered off andwashed with water. The filter residue is dissolved in methanol, the freebase is precipitated by the addition of 30 ml of water and 2N sodiumhydroxide solution. Yield: 4.95 g (66%)

EXAMPLE 6[6-(4-amino-4-methylpiperidin-1-yl)-2-chloro-7,8-dihydropyrimido[5,4-d]pyrimidin-4-yl]-(3-chloro-4-fluorophenyl)amine(6)

[0102] At 60° C. a mixture of 30.8 g (0.270 mol) of4-methylpiperidin-4-ylamine and 100 ml of methanol is added dropwise toa suspension of 100 g (0.257 mol) of (3) in 690 ml of methanol. Themixture is stirred for 1 hour at 60° C., allowed to cool to 40° C., 280ml of 2N sodium hydroxide solution are added and the resulting mixtureis stirred for 3 hours at 60° C. Then 300 ml of methanol are distilledoff and 600 ml of water are added. The mixture is stirred for 5 minutesat ambient temperature, filtered off and the residue is washed with 250ml of water, 3 times 50 ml of acetone and 100 ml ofmethyl-tert-butylether and dried at 40° C. in vacuo. Yield: 100.5 g(92.2%), melting point 211.5° C. 400 MHz-¹H-NMR (DMSO) (ppm)=8,55 br s,1H, NH; 8,05 dd, 1H, aniline-H; 7,78 ddd, 1H, aniline-H; 7,47 t, 1H,aniline-H; 6.90 br s, 1H, NH; 4,28 s, 2H, CH₂; 3,68 m, 2H, CH₂; 3,45 m,2H, CH₂, 3,32 br s, 2H, NH₂; 1,37 m, 4H, 2CH₂; 1,05 s, 3H, CH₃.

EXAMPLE 7[6-(4-amino-4-methylpiperidin-1-yl)-4-(3-chloro-4-fluorophenylamino)-pyrimido[5,4-d]pyrimidine(7)

[0103] Dechlorination:

[0104] A mixture of 80 g (0.182 mol) of (6) in 160 ml glacial aceticacid at 90° C. is added dropwise to a suspension of 11.7 g (0.378 mol)of red phosphorus in 150 ml of hydriodic acid (57%, 1.134 mol). Themixture is refluxed for 4 hours, 5 g of activated charcoal are added,the mixture is then filtered and the residue is washed with glacialacetic acid and water. The filtrate is added dropwise, with vigorousstirring, to a solution of 270 ml water, 270 ml of methanol and 270 mlof sodium hydroxide solution (50%). The mixture is stirred for a further30 minutes at 15° C. and the solid precipitated is filtered off. This iswashed twice with 500 ml of water, then suspended in 500 ml of water,filtered off and dried in vacuo at 45° C. Yield: 65.2 g (91.9%)

[0105] Oxidation, Variant A:

[0106] 0.35 g (0.002 mol) of potassium iodide and 10.9 ml (0.112 mol) of35% hydrogen peroxide are added at boiling temperature to a solution of34 g (0.084 mol) of the dechlorinated compound in 500 ml of water and38.7 ml of concentrated sulphuric acid. The mixture is stirred for 20minutes, a solution of 7 g of sodium bisulphite in 10 ml of water and150 ml of ethanol are added thereto. The mixture is then left to coolslowly to ambient temperature and stirred for another 3 hours. Theproduct that crystallises out is filtered off and dried in vacuo at 40°C. Yield 34.3 g (84.1%) in the form of the sulphate. A suspension of 42g of the sulphate in 600 ml of water and 40 ml of concentrated ammoniasolution is extracted with 1.5 l of ethyl acetate. The combined organicphases are washed with water, dried with sodium sulphate and evaporateddown in vacuo until crystallisation begins. The mixture is stirred for 2hours at 0° C., the product that crystallises out is filtered off anddried in vacuo. Yield: 25.5 g (76.6%).

[0107] Oxidation, Variant B:

[0108] A solution of 8.9 g (0.037 mol) of sodium peroxodisulphate in 25ml of water is added dropwise at ambient temperature to a solution of 10g (0.025 mol) of the dechlorinated compound in 100 ml of water and 5.7ml of glacial acetic acid. The mixture is stirred for 30 minutes at 60°C. and overnight at ambient temperature. Then 200 ml of ethyl acetateand 30 ml of concentrated ammonia solution are added. The phases areseparated, the aqueous phase is extracted with 100 ml of ethyl acetateand the combined organic phases are evaporated to dryness. The residueis taken up in 140 ml of ethyl acetate at boiling temperature, then 80ml of ethyl acetate are distilled off and the residue is cooled to 0° C.The product that crystallises out is filtered off and dried in vacuo.Yield: 6.2 g (63.9%).

What is claimed is:
 1. A process for preparing a4,6-diaminopyrimido[5,4-d]pyrimidine of the formula I,

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, R² denotes anoptionally substituted C₆-C₁₀ aryl group, R³ denotes a hydrogen atom ora C₁-C₆ alkyl group, and R⁴ denotes a hydrogen atom or an optionallysubstituted C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₈ cycloalkyl or a 4- to7-membered, nitrogen-containing heterocyclyl group, or R³ and R⁴together with the nitrogen atom linked to them denote an optionallysubstituted heterocyclyl group, which process comprises the followingsteps: (a) treating a compound of formula II,

 wherein R¹, R², R³, and R⁴ are as herein defined and PG¹ denotes asuitable protecting group, so as to cleave the protecting group, (b)treating the deprotected species formed by the preceding step with areducing agent, to form a reduced intermediate, and (c) treating thereduced intermediate with an oxidising agent, to form the compound ofthe formula I.
 2. The process according to claim 1, wherein theprotecting group is a C₁₋₆ alkylcarbonyl group and it is cleaved bytreating with an aqueous base.
 3. The process according to claim 1,wherein in step (b) the compound obtained after the protecting group hasbeen cleaved is hydrogenated in the presence of a transition metalcatalyst or treated with hydrogen iodide, optionally in the presence ofphosphorus.
 4. The process according to one of claim 1, wherein in step(c) the compound obtained in step (b) is treated with a peroxodisulphateor hydrogen peroxide.
 5. A process for preparing a compound of theformula II

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, R² denotes anoptionally substituted C₆-C₁₀ aryl group, R³ denotes a hydrogen atom ora C₁-C₆ alkyl group, and R⁴ denotes a hydrogen atom or an optionallysubstituted C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₈ cycloalkyl or a 4- to7-membered, nitrogen-containing heterocyclyl group, or R³ and R⁴together with the nitrogen atom linked to them denote an optionallysubstituted heterocyclyl group, and PG¹ denotes a suitable protectinggroup, wherein a compound of the formula III,

wherein R¹, R² and PG¹ are as herein defined, is reacted with an amineof formula IV, R³R⁴NH  (IV) wherein R³ and R⁴ are as herein defined,optionally in the presence of a base.
 6. The process according to claim5, wherein the reaction is carried out in the presence of a tertiaryamine.
 7. The process according to claim 5, wherein the reaction iscarried out in a temperature range of 0° C. to 150° C.
 8. A process forpreparing a compound of the formula III

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, R² denotes anoptionally substituted C₆-C₁₀ aryl group, and PG¹ denotes a suitableprotecting group, wherein a compound of the formula V,

wherein R¹ and R² are as herein defined, is provided with a suitableprotecting group (PG¹).
 9. The process according to claim 8, wherein thecompound of formula V is reacted with a C₁₋₆ carboxylic acid or areactive derivative thereof in the presence of a base.
 10. The processaccording to claim 8, wherein the compound of formula V is reacted witha C₁₋₆ carboxylic acid chloride in the presence of a tertiary amine. 11.Process for preparing a compound of formula V

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, and R²denotes an optionally substituted C₆-C₁₀ aryl group, in which process acompound of the formula VI,

wherein R¹ and R² are as herein defined, is reduced.
 12. The processaccording to claim 11, wherein the reduction is carried out with aboranate.
 13. The process according to claim 12, wherein the reductionis carried out with sodium boranate in the presence of a base and apolar solvent.
 14. A process for preparing a compound of the formula

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, and R²denotes an optionally substituted C₆-C₁₀ aryl group, in which process2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine is reacted with an amine offormula VIII, R¹R²NH  (VIII) wherein R¹ and R² are as herein defined.15. A 2-Chloro-4,6-diamino-7,8-dihydropyrimido[5,4-d]pyrimidine of theformula II

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, R² denotes anoptionally substituted C₆-C₁₀ aryl group, R³ denotes a hydrogen atom ora C₁-C₆ alkyl group, and R⁴ denotes a hydrogen atom or an optionallysubstituted C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₈ cycloalkyl or a 4- to7-membered, nitrogen-containing heterocyclyl group, or R³ and R⁴together with the nitrogen atom linked to them denote an optionallysubstituted heterocyclyl group, and PG¹ denotes a C₁₋₆ alkanoyl group.16. A 4-amino-2,6-dichloro-7,8-dihydropyrimido[5,4-d]pyrimidine of theformula III

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, and R²denotes an optionally substituted C₆-C₁₀ aryl group, and PG¹ denotes aC₁₋₆ alkanoyl group.
 17. A4-amino-2,6-dichloro-7,8-dihydropyrimido[5,4-d]pyrimidine of the formulaV,

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, and R²denotes an optionally substituted C₆-C₁₀ aryl group.
 18. A4-amino-2,6,8-trichloropyrimido[5,4-d]pyrimidine of the formula VI,

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, and R²denotes an optionally substituted C₆-C₁₀ aryl group
 19. A process forpreparing a 4,6-diaminopyrimido[5,4-d]pyrimidine of the formula I,

wherein R¹ denotes a hydrogen atom or a C₁-C₆ alkyl group, R² denotes anoptionally substituted C₆-C₁₀ aryl group, R³ denotes a hydrogen atom ora C₁-C₆ alkyl group, and R⁴ denotes a hydrogen atom or an optionallysubstituted C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₈ cycloalkyl or a 4- to7-membered, nitrogen-containing heterocyclyl group, or R³ and R⁴together with the nitrogen atom linked to them denote an optionallysubstituted heterocyclyl group, which process comprises the followingsteps: (a) reacting 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine with anamine of formula VIII, R¹R²NH  (VIII) (b) reducing the resultingcompound of the formula VI,

wherein R¹ and R² are as herein defined, (c) providing the resultingcompound of the formula V,

wherein R¹ and R² are as herein defined, with a suitable protectinggroup (PG¹); (d) reacting the resulting compound of the formula III,

wherein R¹, R² and PG¹ are as herein defined, with an amine of formulaIV, R³R⁴NH  (IV) wherein R³ and R⁴ are as herein defined, optionally inthe presence of a base; (e) treating the resulting compound of formulaII,

wherein R¹, R², R³, and R⁴ are as herein defined and PG¹ denotes asuitable protecting group, so as to cleave the protecting group, (f)treating the deprotected species formed by the preceding step with areducing agent, to form a reduced intermediate, and (g) treating thereduced intermediate with an oxidising agent, to form the compound ofthe formula I.